1,4- AND 4,10-DIHYDRO-4-OXO-PYRIMIDO (1,2-A)-benzimidazole-3-carboxylic acids, esters and amides

ABSTRACT

New derivatives, and their salts, of 1,4- and 4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylic acids, esters and carboxamides have the general formulas ##STR1## They are useful as central nervous system depressants and anti-inflammatory agents.

SUMMARY OF THE INVENTION

This invention relates to new carboxylic acids, esters and carboxamidesof 1,4- and 4,10-dihydro-4-oxopyrimido[1,2-a]benzimidazole, as well astheir salts. These new compounds have the general formulas ##STR2## and##STR3##

The symbols have the following meanings in the formulas I, II andthroughout this specification.

R¹ is hydrogen, lower alkyl, phenyl-lower alkyl, di-loweralkylamino-lower alkyl, i.e., -lower alkyl ##STR4## wherein R⁴ and R⁵each is lower alkyl. The basic group ##STR5## may also form anunsubstituted or substituted heterocycle ##STR6## in which R⁴ and R⁵join with the nitrogen to complete one of the heterocyclic groups,piperidino, piperazinyl, morpholino, thiamorpholino, each of which mayalso bear as a substituent a hydroxy-lower alkyl group or one or twolower alkyl groups.

R² is hydrogen or lower alkyl.

R³ is hydroxy, lower alkoxy or an amino group ##STR7## wherein R⁶ and R⁷each is hydrogen, lower alkyl, phenyl, substituted phenyl, (wherein thephenyl substituent is halo, lower alkyl or lower alkoxy), phenyl-loweralkyl or di-lower alkylamino-lower alkyl group like the one describedabove for R¹. The basic group ##STR8## may also form an unsubstituted orsubstituted heterocycle of 5 or 6 members, ##STR9## in which R⁶ and R⁷join with the nitrogen to complete a heterocyclic group in which anadditional hetero atom is present, i.e., pyrrolidino, piperidino,piperazinyl, morpholino, thiamorpholino, each of which may bear as asubstituent a hydroxy-lower alkyl group of one or two lower alkylgroups.

DETAILED DESCRIPTION OF THE INVENTION

The groups represented by the symbols have the following meaningsthroughout this specification.

The lower alkyl groups are straight or branched chain hydrocarbon groupsin the series from methyl to heptyl having up to seven carbons, likemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like.The C₁ -C₄ members are preferred and the C₁ -C₂ members are especiallypreferred.

The lower alkoxy groups include similar alkyl groups to which an oxygenis attached. The same C₁ -C₄ and C₁ -C₂ preferences apply.

The phenyl-lower alkyl groups include similar alkyl groups to which aphenyl ring is attached. The phenyl-(C₁ -C₄) lower alkyl and phenyl-(C₁-C₂) lower alkyl groups similarly constitute preferred and especiallypreferred groups.

The substituted phenyl groups include such radicals as halophenyl, e.g.,o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, etc., o-, m- orp-tolyl, o-, m- or p-methoxyphenyl and the like.

The halogens are the four common halogens, chlorine and bromine beingpreferred, especially the first.

The amino groups represented by the radical ##STR10## include amino,lower alkylamino groups like methylamino, ethylamino, propylamino,isopropylamino, etc., or di-(lower alkyl)amino groups likedimethylamino, diethylamino, dipropylamino, methylethylamino and thelike, or groups like anilino, phenylmethylamino, phenylethylamino,p-methoxyphenylamino, etc. A di-lower alkylamino-lower alkyl group mayalso be present on the nitrogen forming such groups as dimethylaminomethylamino, dimethylaminoethylamino, diethylaminomethylamino,diethylaminoethylamino, dipropylaminoethylamino,methyl(ethyl)aminoethylamino, and the like. The di-loweralkylamino-lower alkyl groups represented by R¹ are similar groups withbut one nitrogen. The lower alkyl groups in each of the foregoingradicals is preferably C₁ -C₄ and C₁ -C₂ as described above. Preferablyalso the ##STR11## group includes only one phenyl, substituted phenyl,phenyl-lower alkyl or di-lower alkylamino-lower alkyl group, i.e., R⁶ isphenyl, substituted phenyl, phenyl-lower alkyl or di-loweralkylamino-lower alkyl and R⁷ is then hydrogen. In addition, in any ofthe di-lower alkyl groups, preferably but not necessarily, both loweralkyl groups in a given compound are the same.

The ##STR12## can also represent a heterocyclic radical of the groupdescribed wherein the R's join to complete the heterocycle, e.g.,piperidino, pyrrolidino, piperazinyl, lower alkylpiperidino, e.g., 2-,3- or 4-methylpiperidino, (preferably 4-methylpiperidino), 2-, 3- or4-ethylpiperidino, etc., lower alkylpiperazinyl, e.g.,4-methylpiperazin-1-yl (which is preferred), 4-ethylpiperazin-1-yl,etc., or (hydroxy-lower alkyl)piperazinyl, e.g.,4-hydroxyethylpiperazin-1-yl, and the like.

The products of the examples, which are representative of the variouscompounds of this invention, constitute preferred embodiments.Especially preferred compounds of the formulas I and II are thosewherein R¹ is lower alkyl, especially ethyl, R² is lower alkyl orhydrogen, especially hydrogen, R³ is hydroxy, lower alkoxy, loweralkylamino, especially butylamino.

The new isomeric compounds of the formulas I and II are formed by thefollowing series of reactions. The symbols in the structural formulashave the same meaning as previously described.

An alkoxymethylenemalonic acid ester of the formula ##STR13## is made toreact with a 2-aminobenzimidazole of the formula ##STR14##

The reaction is accomplished at 120°-130° in a solvent likedimethylformamide, acetic acid, or the like. A product of the formula##STR15## is formed. This compound is now alkylated with an alkyl halideR¹ -hal, wherein hal represents halogen, preferably iodine, chlorine orbromine, in a solvent like dimethylformamide and in the presence of abase like potassium carbonate or the like, at about 80° C over a periodof 2 to 3 days. This reaction results in the formation of a mixture ofthe isomeric compounds of formulas Ia and IIa: ##STR16##

These isomeric products can be separated by repeated crystallizationfrom acetone, dimethylformamide or the like or by chromatography onsilica gel, alumina or the like. Compounds of the formula Ia are moresoluble in the acetone, dimethylformamide, etc.

Compounds of the formula ##STR17## and compounds of the formula##STR18## with a carboxamide function are obtained by treating thecompound of formula Ia or IIa, respectively, with an appropriatelysubstituted amine of the formula ##STR19## The reaction proceeds at atemperature of about 80° to 120° C. Sometimes, when low boiling aminesare used, the reaction is run in an autoclave.

In an alternative procedure, compounds of formulas Ib or IIb areobtained by treatment of a compound of formulas Ia or IIa, respectively,with a base like potassium hydroxide or sodium hydroxide in aqueousmethanol. By this reaction an acid of the formula ##STR20## is obtained.The acid is refluxed with an inorganic acid chloride like phosphorusoxychloride or thionyl chloride. An acid chloride of the formula##STR21## is formed. The compound of formula Ib or IIb is now obtainedby reaction of the compound of formulas Id or IId with the amine offormula VI.

The new compounds of formula I form salts which are also part of thisinvention. The salts include acid addition salts, particularly thenon-toxic, physiologically acceptable members. These salts are formed byreaction with one or more equivalents of any of a variety of inorganicand organic acids providing acid addition salts including, for example,hydrohalides (especially hydrochloride and hydrobromide), sulfate,nitrate, borate, phosphate, oxalate, tartrate, malate, citrate, acetate,ascorbate, succinate or aryl- or alkanesulfonates like benzenesulfonate,methanesulfonate and toluenesulfonate, or cyclohexanesulfamate. The acidaddition salts frequently provide a convenient means for isolating theproduct, e.g., by forming and precipitating a salt (which is notnecessarily non-toxic) in an appropriate medium in which the salt isinsoluble, then after separation of the salt, neutralizing with a basesuch as barium hydroxide or sodium hydroxide, to obtain the free base offormula I. Other salts can then be formed from the free base by reactionwith one or more equivalents of acid containing the desired anion.

Additional experimental details are found in the examples.

The new compounds of this invention are central nervous systemdepressants which can be used as psychotropic agents, e.g., as ataracticagents for the relief of anxiety and tension states, for example, inmice, cats, rats, dogs and other mammalian species. For this purpose acompound or mixture of compounds of formula I, or non-toxic,physiologically acceptable acid addition salt thereof, is preferablyadministered orally, but parenteral routes such as subcutaneously,intramuscularly, intravenously or intraperitoneally in the describeddosages, can also be employed. A single dose, or preferably 2 to 4divided daily doses, provided on a basis of about 1 to 50 mg. perkilogram per day, preferably about 2 to 15 mg. per kilogram per day, isrecommended.

The new compounds of this invention also have anti-inflammatoryproperties and are useful as anti-inflammatory agents, for example, toreduce local inflammatory conditions such as those of an edematousnature or resulting from proliferation of connective tissue in variousmammalian species such as rats, dogs and the like when given orally indosages of about 5 to 50 mg. per kilogram per day, preferably 5 to 25mg. per kilogram per day, in single or 2 to 4 divided doses, asindicated by the carageenan edema assay or delayed hypersensitivityreaction test in rats.

The compounds of the invention can be utilized by formulating incompositions such as tablets, capsules or elixirs for oraladministration or in sterile solutions or suspensions for parenteraladministration. About 10 to 300 mg. of a compound or mixture ofcompounds of formula I or physiologically acceptable acid addition saltis compounded with a physiologically acceptable vehicle, carrier,excipient, binder, preservative, stabilizer, flavor, etc., in a unitdosage form as called for by accepted pharmaceutical practice. Theamount of active substance in these compositions or preparations is suchthat a suitable dosage in the range indicated is obtained.

The following examples are illustrative of the invention. They alsoserve as models for the preparation of other members of the group whichcan be produced by suitable substitution of starting materials. Alltemperatures are in degrees celsius.

EXAMPLE 110-Ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, ethyl ester and1-Ethyl-1,4-dihydro-4-oxopyrimido[1,2-a]benzimidazole-3-carboxylic acid,ethyl ester (a) 4-Hydroxypyrimido[1,2-d]benzimidazole-3-carboxylic acid,ethyl ester

266 g. of 2-aminobenzimidazole (2 mol.) and 432 g. of ethoxymethylenemalonic acid diethyl ester are heated with stirring in 3 liters of DMFat 80° for 3 hours. The solution is cooled to room temperature and thenfiltered off and the crystalline4-hydroxypyrimido[1,2-a]-benzimidazole-3-carboxylic acid, ethyl ester isrecrystallized from acetic acid, yield 490 g. (95%); m.p. 309°-310°.

(b)10-Ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, ethyl ester and1-Ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, ethyl ester

257 g. of 4-hydroxypyrimido[1,2-a]benzimidazole-3-carboxylic acid, ethylester (1 mol.), 204.5 g. of ethyl iodide (1.3 mol.) and 182 g. ofpotassium carbonate are heated in 1.5 liters of DMF with stirring at 80°for 72 hours. The insoluble inorganic material is removed by filtrationand about 1 liter of water is added to the filtrate. A mixture of thetwo title compounds crystallizes and is filtered off and dried at 60°.The crystalline mixture is now dissolved in hot acetone and allowed tostand until the temperature reaches about 22°. The precipitated1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylicacid, ethyl ester is filtered off and recrystallized from acetone, yield99 g. (35%); m.p. 211°-213°.

The mother liquors are combined, evaporated to dryness and dissolved inhot acetone. The solution is cooled to about 20° and allowed to standfor 1 hour. A mixture of the two compounds is obtained (about 12 g.) andfiltered off. The filtrate is cooled in an ice bath and the precipitated10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylicacid, ethyl ester is filtered off (purity about 90%); m.p. 158°-160°;yield 92 g. (32%). This compound is pure enough for further reactions.For further purification, the compound is recrystallized about 3 timesfrom hot acetone until the melting point has reached 160°-161°.

By following the above procedure, substituting for the ethyl iodide inpart b the indicated alkyl halide, the following products are obtained:##STR22##

    ______________________________________                                             Com-                                                                     Ex.  pound   Alkylhalide  R.sup.1     m.p.                                    ______________________________________                                        2   A      BrCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                       CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                      123-125°                         2   B      BrCH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                       CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                      134-136                                 3   A      BrC.sub.3 H.sub.7                                                                            C.sub.3 H.sub.7                                                                           155-158                                 3   B      BrC.sub.3 H.sub.7                                                                            C.sub.3 H.sub.7                                                                           158-161                                 4   A      ICH.sub.3      CH.sub.3    172-175                                 4   B      ICH.sub.3      CH.sub.3    233-235                                 5   A                                                                                                    ##STR23##  188-190                                 5   B                                                                                     ##STR24##                                                                                    ##STR25##  186-187                                 6   A      ClCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               CH.sub.2).sub.3 N(CH.sub.3).sub.2                                                         142-143                                 6   B      ClCH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                               CH.sub.2).sub.3 N(CH.sub.3).sub.2                                                         125-126                                 ______________________________________                                    

EXAMPLE 7N-Butyl-10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide

8 g. of 90% pure10-ethyl-4,10-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylicacid, ethyl ester produced as in Example 1b are refluxed with stirringin 30 ml. of n-butylamine for 12 hours. The solution is allowed to coolto room temperature. A small amount of precipitated isomericN-butyl-1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide(m.p. 232°-234° ) is filtered off and the mother liquor evaporated todryness. The remainingN-butyl-10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamideis recrystallized from ethyl acetate, m.p. 118°-120°, yield 6.5 g.(74%).

The hydrochloride salt is produced by treating the above product withethanolic HCl and recrystallizing from propylene glycol, m.p. 124°-126°.

By following the above procedure of Example 7, substituting for thebutylamine the indicated amine, the following additional products areobtained:

    __________________________________________________________________________     ##STR26##                                                                    Ex.                                                                              R.sup.1  Amine     R        m.p. Yield                                     __________________________________________________________________________     8 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                                   H.sub.2 NC.sub.4 H.sub.9                                                                C.sub.4 H.sub.9                                                                        112-123°                                                                    77%                                        9 C.sub.2 H.sub.5                                                                        H.sub.2 NCH(CH.sub.3)C.sub.2 H.sub.5                                                    CH(CH.sub.3)C.sub.2 H.sub.5                                                            108-110                                                                            68%                                       10 CH.sub.3 H.sub.2 NC.sub.4 H.sub.9                                                                C.sub.4 H.sub.9                                                                        175-177                                                                            81%                                       11 C.sub.3 H.sub.7                                                                        H.sub.2 NC.sub.4 H.sub.9                                                                C.sub.4 H.sub.9                                                                        211-212                                                                            69%                                       12 C.sub.2 H.sub.5                                                                         ##STR27##                                                                               ##STR28##                                                                             115-117                                                                            80%                                       13 C.sub.2 H.sub.5                                                                        H.sub.2 N(CH.sub.2).sub.3 N(CH.sub.3).sub.2                                             (CH.sub.2).sub.3 N(CH.sub.3).sub.2                                                     80-82                                                                              71%                                       __________________________________________________________________________

The compounds of Examples 8-13 are recrystallized from ethyl acetate.The isomeric 1-substituted compound is obtained from the mother liquor.

EXAMPLE 14N-Butyl-1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamid

10 g. of1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylicacid, ethyl ester obtained as in Example 1b are refluxed with 50 ml. ofn-butylamine for 12 hours with stirring. TheN-butyl-1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamideis filtered off after cooling, yield 8.3 g. (76%); m.p. 232°-234°(DMF/H₂ O).

By following the above procedure of Example 14 substituting for thebutylamine the indicated amine, the following additional products areobtained:

    __________________________________________________________________________     ##STR29##                                                                    Ex.                                                                              R.sup.1 Amine     R        m.p.  Yield                                     __________________________________________________________________________    15 CH.sub.3                                                                              H.sub.2 NC.sub.4 H.sub.9                                                                C.sub.4 H.sub.9                                                                        266-267°                                                                    88%                                        16 C.sub.2 H.sub.5                                                                       H.sub.2 NCH(CH.sub.3)C.sub.2 H.sub.5                                                    CH(CH.sub.3)C.sub.2 H.sub.5                                                            260-261                                                                            85%                                        17 C.sub.3 H.sub.7                                                                       H.sub.2 NC.sub.4 H.sub.9                                                                C.sub.4 H.sub.9                                                                        219-221                                                                            81%                                        18                                                                                ##STR30##                                                                            H.sub.2 NC.sub.4 H.sub.9                                                                C.sub.4 H.sub.9                                                                        242-243                                                                            75%                                        __________________________________________________________________________

The compounds of Examples 15-18 are recrystallized from DMF.

EXAMPLE 1910-Ethyl-4,10-dihydro-N-methyl-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide

10 g. of 90% pure10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylicacid, ethyl ester produced in Example 1b are dissolved in 50 ml. ofalcohol. After addition of 10 ml. of methylamine, the solution is heatedin an autoclave at 100° for 12 hours. After this time, the solvent isdistilled off and the crystalline residue is heated with hot acetone.The small amount of isomeric1-ethyl-1,4-dihydro-N-methyl-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamideis insoluble and is filtered off. After addition of water to the motherliquor, the10-ethyl-4,10-dihydro-N-methyl-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxamidecrystallizes, yield 63%; m.p. 178°-180° (acetone).

By following the above procedure of Example 19, the following additionalproducts are obtained:

    ______________________________________                                         ##STR31##                                                                    Example                                                                              R.sup.1     Amine    R     m.p.   Yield                                ______________________________________                                        20     CH.sub.3    H.sub.2 NCH.sub.3                                                                      CH.sub.3                                                                            180-182°                                                                      68%                                                                    (DMF)                                       21                                                                                    ##STR32##  H.sub.2 NCH.sub.3                                                                      CH.sub.3                                                                            165-167 (DMF)                                                                        70%                                  ______________________________________                                    

EXAMPLE 221-Ethyl-1,4-dihydro-N-methyl-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide

10 g. of1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, ethyl ester produced as in Example 1b are heated at 120° in butylalcohol with 10 ml. of methylamine in an autoclave for 12 hours. Thesolvent is distilled off and the residue recrystallized from DMF, yield88%; m.p. 270°-272°.

The following products are obtained by the procedure of Example 22:

    ______________________________________                                         ##STR33##                                                                    Example                                                                              R.sup.1     Amine    R     m.p.   Yield                                ______________________________________                                        23     CH.sub.3    H.sub.2 NCH.sub.3                                                                      CH.sub.3                                                                            325-326°                                                                      65%                                                                    (DMF)                                       24                                                                                    ##STR34##  H.sub.2 NCH.sub.3                                                                      CH.sub.3                                                                            280-283 (DMF)                                                                        71%                                  ______________________________________                                    

EXAMPLE 2510-Ethyl-3-[(4-morpholinyl)carbonyl]pyrimido[1,2-a]benzimidazole-4-(10H)-one(a)10-Ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid

28.5 g. of pure10-ethyl-4,10-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylicacid, ethyl ester produced as in Example 1b are stirred in a solution of7 g. of potassium hydroxide in 200 ml. of alcohol for 15 hours at roomtemperature. After this time, the solvent is distilled in vacuo and theresidue dissolved in 200 ml. of water and acidified with acetic acid.10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid precipitates and is filtered off, yield 20 g. (79%); m.p. 228°-230°(DMF).

(b) 10-Ethyl-3-[(4-morpholinyl)carbonyl]pyrimido[1,2-a]benzimidazole-4(10H)-one

2.6 g. of10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylicacid is refluxed with stirring in 20 ml. of thionyl chloride. The excessthionyl chloride is distilled off, the remaining residue treated with 10ml. of toluene and again evaporated to dryness. The crystalline acidchloride is now suspended in 20 ml. of toluene and 2 g. of morpholineare added and the reaction mixture is stirred overnight. Afterevaporation of the solvent, the residue is treated with 10 ml. of waterand filtered off. Recrystallization from ethyl acetate yields 2.5 g. of10-ethyl-3-[(4-morpholinyl)-carbonyl]pyrimido[1,2-a]benzimidazole-4(10H)-one;m.p. 200°-202°.

By following the above procedure of Example 26, substituting theappropriate amine, the following additional products are obtained:

    __________________________________________________________________________     ##STR35##                                                                    Example                                                                            R.sup.1   R.sup.3    m.p.    Yield                                       __________________________________________________________________________     26a CH.sub.3  OH                                                              26b CH.sub.3                                                                                 ##STR36## 213-216°                                                                       59%                                                                   (ethylacetate)                                      27   CH.sub.3                                                                                 ##STR37## 288-290 63%                                                                   (DMF/H.sub.2 O)                                     28   C.sub.2 H.sub.5                                                                          ##STR38## 188-190 72%                                                                   (ethylacetate)                                      29   C.sub.2 H.sub.5                                                                          ##STR39## 145-147 70%                                                                   (ethylacetate)                                      30   C.sub.2 H.sub.5                                                                          ##STR40## 180-182 73%                                                                   (ethylacetate)                                      31                                                                                  ##STR41##                                                                               ##STR42## 241-242 68%                                                                   (DMF)                                               32                                                                                  ##STR43##                                                                               ##STR44## 203-205 65%                                                                   (DMF)                                               __________________________________________________________________________

EXAMPLE 331-Ethyl-1,4-dihydro-4-oxo-N-phenyl-pyrimido[1,2-a]benzimidazole-3-carboxamide(a) 1-Ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid

28.5 g. of1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylicacid, ethyl ester produced as in Example 1b are heated with stirring ina solution of 7 g. of potassium hydroxide in 200 ml. of alcohol for 15hours at 80°. The solvent is removed in vacuo and the residue dissolvedin 200 ml. of water and acidified with acetic acid.1-Ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylic acidprecipitates and is filtered off, yield 81%; m.p. 252°-253°.

EXAMPLE 39N-Butyl-10-morpholinoethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxamideandN-butyl-1-morpholinoethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide

By substituting morpholinoethyl chloride for the dimethylaminopropylchloride in the procedure of Example 6 and subjecting the products,respectively, to the procedure of Examples 7 and 14,N-butyl-10-morpholinoethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamideand N-butyl-1-morpholinoethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide, respectively, areobtained.

By following the above procedure of Example 39 and substituting for themorpholinoethyl chloride the indicated aminoalkyl halide and for thebutylamine the indicated amine, the following additional products areobtained:

    __________________________________________________________________________     ##STR45##                                                                                             ##STR46##                                            Example                                                                              Aminoalkyl halide                                                                              Amine R.sup.1           R.sup.3                       __________________________________________________________________________    40   A                                                                                ##STR47##       HN(CH.sub.3).sub.2                                                                   ##STR48##        N(CH.sub.3).sub.2                  B                                                                                ##STR49##       HN(CH.sub.3).sub.3                                                                   ##STR50##        N(CH.sub.3).sub.2             41   A                                                                                ##STR51##       H.sub.2 NC.sub.2 H.sub.5                                                             ##STR52##        NHC.sub.2 H.sub.5                  B                                                                                ##STR53##       H.sub.2 NC.sub.2 H.sub.5                                                             ##STR54##        NHC.sub.2 H.sub.5             42   A                                                                                ##STR55##       H.sub.2 NC.sub.3 H.sub.7                                                             ##STR56##        NHC.sub.3 H.sub.7                  B                                                                                ##STR57##       H.sub.2 NC.sub.3 H.sub.7                                                             ##STR58##        NHC.sub.3 H.sub.7             43   A                                                                                ##STR59##       H.sub. 2 NCH.sub.3                                                                   ##STR60##        NHCH.sub.3                         B                                                                                ##STR61##       H.sub.2 NCH.sub.3                                                                    ##STR62##        NHCH.sub.3                    44   A                                                                                ##STR63##       H.sub.2 NC.sub.4 H.sub.9                                                             ##STR64##        NHC.sub.4 H.sub.9                  B                                                                                ##STR65##       H.sub.2 NC.sub.4 H.sub.9                                                             ##STR66##        NHC.sub.4 H.sub.9             __________________________________________________________________________

EXAMPLE 45N-[3-(Dimethylamino)propyl]-1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-4-carboxamide

By substituting 3-(dimethylamino)propylamine for the n-butylamine in theprocedure of Example 14,N-[3-(dimethylamino)-propyl]-1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-4-carboxamideis obtained, m.p. 225°-227°.

EXAMPLE 461-Benzyl-3-(4-morpholinylcarbonyl)pyrimido[1,2-a]benzimidazole-4 (1H)one

By substituting1-benzyl-1,4-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylicacid ethyl ester in part a and morpholine in part b of Example 33,1-benzyl-3-(4-morpholinylcarbonyl)pyrimido[1,2-a]benzimidazole-4 (1H)oneis obtained.

The following additional compounds are obtained by the procedure ofExample 33.

    ______________________________________                                         ##STR67##                                                                    Ex.   R.sup.1      R.sup.2  R.sup.3                                           ______________________________________                                        47    C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                                                         ##STR68##                                        48    CH.sub.3     CH.sub.3                                                                                ##STR69##                                        49    CH.sub.3     C.sub.2 H.sub.5                                                                        OH                                                50    C.sub.2 H.sub.5                                                                            H                                                                                       ##STR70##                                        51    C.sub.2 H.sub.5                                                                            H                                                                                       ##STR71##                                        52    CH.sub.3     CH.sub.3                                                                                ##STR72##                                        53                                                                                   ##STR73##   CH.sub.3                                                                                ##STR74##                                        ______________________________________                                    

EXAMPLE 5410-Ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, methyl ester and1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, methyl ester

By substituting methoxymethylenemalonic acid dimethyl ester for theethoxymethylenemalonic acid diethyl ester in the procedure of Example 1,10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, methyl ester and1-ethyl-1,4-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid, methyl ester, respectively, are obtained.

EXAMPLE 55

By substituting the indicated amine for the n-butylamine in theprocedures of Examples 7 (product A) or 14 (product B), respectively,the following products are obtained:

    __________________________________________________________________________     ##STR75##                                                                                          ##STR76##                                               Example                                                                            Amine     Compound                                                                            R.sup.1                                                                             R.sup.2                                                                           R                                              __________________________________________________________________________    56   HN(C.sub.3 H.sub.7).sub.2                                                                A    C.sub.2 H.sub.5                                                                     H   N(C.sub.3 H.sub.7).sub.2                            HN(C.sub.3 H.sub.7).sub.2                                                                B    C.sub.2 H.sub.5                                                                     H   N(C.sub.3 H.sub.7).sub.2                       57   NH.sub.3   A    C.sub.2 H.sub.5                                                                     H   NH.sub.2                                            NH.sub.3   B    C.sub.2 H.sub.5                                                                     H   NH.sub.2                                       58                                                                                  ##STR77## A    C.sub.2 H.sub.5                                                                     CH.sub.3                                                                           ##STR78##                                           ##STR79## B    C.sub.2 H.sub.5                                                                     CH.sub.3                                                                           ##STR80##                                     59   HN(CH.sub.3).sub.2                                                                       A    CH.sub.3                                                                            CH.sub.3                                                                          N(CH.sub.3).sub.2                                   HN(CH.sub.3).sub.2                                                                       B    CH.sub.3                                                                            CH.sub.3                                                                          N(CH.sub.3).sub.2                              60                                                                                  ##STR81## A    C.sub.2 H.sub.5                                                                     H                                                                                  ##STR82##                                           ##STR83## B    C.sub.2 H.sub.5                                                                     H                                                                                  ##STR84##                                     61                                                                                  ##STR85## A    C.sub.2 H.sub.5                                                                     H                                                                                  ##STR86##                                           ##STR87## B    C.sub.2 H.sub.5                                                                     H                                                                                  ##STR88##                                     62                                                                                  ##STR89## A    C.sub.2 H.sub.5                                                                     CH.sub.3                                                                           ##STR90##                                           ##STR91## B    C.sub.2 H.sub.5                                                                     CH.sub.3                                                                           ##STR92##                                     __________________________________________________________________________

EXAMPLE 6310-Benzyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid

By substituting benzyl bromide for the ethyl iodide in the procedure ofExample 1b and then hydrolyzing the product by the procedure of Example25 a,10-benzyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylicacid is obtained.

What is claimed is:
 1. A compound of the formula ##STR93## wherein R¹ ishydrogen, lower alkyl, phenyl-lower alkyl or lower alkyl ##STR94## R² ishydrogen or lower alkyl; R³ is hydroxy, lower alkoxy or ##STR95## R⁴ andR⁵ each is lower alkyl; R⁶ and R⁷ each is hydrogen, lower alkyl, phenyl,substituted phenyl wherein the phenyl substituent is halo, lower alkylor lower alkoxy or phenyllower alkyl; and physiologically acceptablesalts thereof.
 2. A compound of the formula ##STR96## wherein R¹, R² andR³ have the same meaning as in claim 1, and physiologically acceptablesalts thereof.
 3. A compound as in claim 1 wherein R² is hydrogen.
 4. Acompound as in claim 2 wherein R² is hydrogen.
 5. A compound as in claim1 wherein R¹ is lower alkyl; R² is hydrogen or lower alkyl; R³ ishydroxy, lower alkoxy or lower alkylamino, and physiologicallyacceptable salts thereof.
 6. A compound as in claim 2 wherein R¹ islower alkyl; R² is hydrogen or lower alkyl; R³ is hydroxy, lower alkoxyor lower alkylamino, and physiologically acceptable salts thereof.
 7. Acompound as in claim 1 wherein R³ is lower alkoxy.
 8. A compound as inclaim 1 wherein R³ is lower alkylamino.
 9. A compound as in claim 1wherein R¹ is lower alkyl; R² is hydrogen and R³ is lower alkoxy.
 10. Acompound as in claim 1 wherein R¹ is lower alkyl; R² is hydrogen and R³is lower alkylamino.
 11. A compound as in claim 2 wherein R¹ is loweralkyl; R² is hydrogen and R³ is lower alkoxy.
 12. A compound as in claim2 wherein R¹ is lower alkyl; R² is hydrogen and R³ is lower alkylamino.13. A compound as in claim 1 wherein R¹ is ethyl; R² is hydrogen and R³is hydroxy.
 14. A compound as in claim 1 wherein R¹ is ethyl; R² ishydrogen and R³ is ethoxy.
 15. A compound as in claim 1 wherein R¹ isethyl; R² is hydrogen and R³ is butylamino.
 16. A compound as in claim 2wherein R¹ is ethyl; R² is hydrogen and R³ is hydroxy.
 17. A compound asin claim 2 wherein R¹ is ethyl; R² is hydrogen and R³ is ethoxy.
 18. Acompound as in claim 2 wherein R¹ is ethyl; R² is hydrogen and R³ isbutylamino.